The present invention relates to a novel intermediate for the preparation of 16.beta.-ethyl steroids of the estrane series having antiestrogenic and antiandrogenic activities, as well as a process for the preparation thereof.
It is known that 17.beta.-hydroxy-16.beta.-ethyl-4-estren-3-one is a medicinal agent effective for the treatment of benign hypertrophy of the prostate (G. Goto et al., Chem. Pharm. Bull. 26: 1718 [1978]). Furthermore, 16.beta.-ethylestradiol seems promising for the treatment of hormone-dependent tumors. (M. K. Agarwal, Antihormones, Elsevier North-Holland, Amsterdam 1979, p. 307).
These compounds can be prepared in a 10-stage process from 3-methoxy-1,3,5(10)-estratrien-17-one as starting material. In this process, 3-methoxy-1,3,5(10)-estratrien-17-one is enolized and acylated with acetic anhydride. The thus-obtained .DELTA..sup.16 -enol acetate is epoxidized with m-chloroperbenzoic acid and split in the presence of acetic acid. The resultant 16.alpha.-acetoxy-3-methoxy-1,3,5(10)-estratrien-17-one is saponified with sodium hydroxide solution in methanol and rearranged into 17.beta.-hydroxy-3-methoxy-1,3,5(10)-estratrien-16-one. Subsequent Grignard reaction with ethylmagnesium iodide yields 3-methoxy-16,17.beta.-dihydroxy-16.alpha.-ethyl-1,3,5(10)-estratriene, which is partially esterified with acetic anhydride/pyridine. The thus-obtained 3-methoxy-17.beta.-acetoxy-16.beta.-hydroxy-16.alpha.-ethyl-1,3,5(10)-estr atriene is subjected to a Serini reaction with zinc/toulene and heating. The resultant 3-methoxy-16.beta.-ethyl-1,3,5(10)-estratrien-17-one is reduced with sodium borohydride in ethanol. The ensuing 3-methoxy-16.beta.-ethyl-1,3,5(10)-estratrien-17.beta.-ol is reduced with lithium in liquid ammonia and then treated with hydrochloric acid/methanol, yielding the desired 17.beta.-hydroxy-16.beta.-ethyl-4-estren-3-one in a yield of barely 20% of theory.
This process has the obvious disadvantage that it requires a large number of stages and leads to relatively low yields due to the complicated synthetic path.